1. Field of the Invention
The present invention generally relates to a series of compounds, to pharmaceutical compositions containing the compounds, and to use of the compounds and compositions as therapeutic agents. More specifically, compounds of the present invention are hexahydroazepinoindole and octahydroazepinoindole compounds. These compounds are serotonin receptor (5-HT) ligands and are useful for treating diseases, disorders, and conditions wherein modulation of the activity of serotonin receptors (5-HT) is desired (e.g. anxiety, depression and obesity).
2. Brief Description of Related Technology
Serotonin has been implicated in a number of diseases, disorders, and conditions that originate in the central nervous system, including diseases, disorders, and conditions related to, for example, sleeping, eating, perceiving pain, controlling body temperature, controlling blood pressure, depression, anxiety, and schizophrenia. Serotonin also plays an important role in peripheral systems, such as the gastrointestinal system, where it has been found to mediate a variety of contractile, secretory, and electrophysiologic effects.
Because of the broad distribution of serotonin within the body, a heightened interest exists for drugs that affect serotonergic systems. In particular, agonists, partial agonists, and antagonists of serotonergic systems are of interest for the treatment of a wide range of disorders, including anxiety, depression, hypertension, migraine, obesity, compulsive disorders, schizophrenia, autism, neurodegenerative disorders (e.g., Alzheimer""s disease, Parkinsonism, and Huntington""s chorea), and chemotherapy-induced vomiting.
The major classes of serotonin receptors (5-HT1-7) contain fourteen to eighteen separate receptors that have been formally classified. See Glennon, et al., Neuroscience and Behavioral Reviews, 1990, 14, 35; and D. Hoyer, et al. Pharmacol. Rev. 1994, 46, 157-203.
For example, the 5-HT2 family of receptors contains 5-HT2A, 5-HT2B, and 5-HT2C subtypes, which have been grouped together on the basis of primary structure, secondary messenger system, and operational profile. All three 5-HT2 subtypes are G-protein coupled, activate phospholipase C as a principal transduction mechanism, and contain a seven-transmembrane domain structure. There are distinct differences in the distribution of the three 5-HT2 subtypes in a mammal. The 5-HT2B and 5-HT2A receptors are widely distributed in the peripheral nervous system, while the 5-HT2C receptor has been found only in the central nervous system, being highly expressed in many regions of the human brain. See G. Baxter, et al. Trends in Pharnacol. Sci. 1995, 16, 105-110.
Subtype 5-HT2A has been associated with effects including vasoconstriction, platelet aggregation, and bronchoconstriction, while subtype 5-HT2C has been associated with diseases that include depression, anxiety, obsessive compulsive disorder, panic disorders, phobias, psychiatric syndromes, and obesity. Very little is known about the pharmocologic role of the 5-HT2B receptor. See F. Jenck, et al., Exp. Opin. Invest. Drugs, 1998, 7, 1587-1599; M. Bos, et al., J. Med. Chem., 1997, 40, 2762-2769; J. R. Martin, et al., The Journal of Pharmacology and Experimental Therapeutics, 1998, 286, 913-924; S. M. Bromidge, et al., J. Med. Chem., 1998, 41, 1598-1612; G. A. Kennett, Drugs, 1998, 1, 4, 456-470; and A. Dekeyne, et al., Neuropharmacology, 1999, 38, 415-423.
U.S. Pat. Nos. 3,553,232 and 3,622,673 disclose 4-(1,4,5,6-tetrahydroazepine[4,5-b]indole-3(2H)-yl) butyrophenones that are reported to be useful in the treatment of mental or emotional disorders.
U.S. Pat. Nos. 3,652,588, 3,676,558, and 3,839,357 disclose 6-alkyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indoles and aneroxigenic compounds thereof that are reportedly useful to tranquilize and otherwise sedate mammals or suppress hunger in mammals.
U.S. Pat. No. 3,525,750 discloses 1,2,3,4,5,6-hexahydroazepino[4,5-b]indoles that are reported to produce an antitussive effect in mammals.
European Patent Application EP 466548A, and counterpart Australian Patent Application Number AU-B-79293/91, disclose substituted hexahydroazepino[4,5-b]indoles that are reported to be useful for treating certain specified central nervous system disorders.
European Patent Specification 0 028 381 reports certain 6-phenyl substituted 1,2,3,4,5,6-hexahydroazepino[4,5-b]indoles that are reported to exhibit anti-depressant, anti-allergic, and neuroleptic activity.
JP Public Patent Disclosure Bulletin Number 63-163347 discloses indole compounds that are reported to prevent fading of organic coloring substances.
International Patent Application Publication Number WO 01/0573 A1 discloses 9-arylsulfone-1,2,3,4,5,6-hexahydroazepino[4,5-b]indoles that are reported to be useful for treating depression, obesity, and other CNS disorders.
Despite the above-cited publications, there remains a need for pharmaceutical agents that are useful in treating a variety of diseases, disorders, and conditions that are associated with serotonin (5-HT) receptors.
Generally, the present invention is directed to methods and compositions useful in treating a disease, disorder, and/or condition in a mammal wherein a 5-HT receptor is implicated, and modulation of a 5-HT function is desired, by using a novel compound disclosed herein.
In accordance with the present invention, novel compounds which demonstrate useful biological activity, and particularly activity as 5-HT receptor ligands, are provided. More specifically, the invention provides a compound of Formula (I): 
wherein R1 is selected from the group consisting of hydrogen, C1-8alkyl, and C1-8hydrocarbylene Ar;
each R2, independently, is selected from the group consisting of C1-8alkyl, and OH;
R3 is hydrogen, C1-8alkyl, Ar, Het, R7C(xe2x95x90O)xe2x80x94, R7OC(xe2x95x90O)xe2x80x94, R5R6NC(xe2x95x90O)xe2x80x94, R7C(xe2x95x90S)xe2x80x94, R7SC(xe2x95x90O)xe2x80x94, R5R6NC(xe2x95x90S)xe2x80x94, R7SO2xe2x80x94, R5R6NSO2xe2x80x94, R7S(xe2x95x90O)xe2x80x94, R5R6NS(xe2x95x90O)xe2x80x94, RcC1-8hydrocarbylene-, or RcC1-8hydrocarbyleneC(xe2x95x90O)xe2x80x94;
each R4, independently, is selected from the group consisting of Ar, C1-8alkyl, ArOxe2x80x94, C1-8alkoxy, Het, halo, OH, CN, NO2, CF3, CF3O, NRaRb, Nxe2x95x90NRaRb, R7S, C1-8hydrocarbyleneAr, and C1-8hydrocarbyleneORa;
each R5 and R6 is independently hydrogen, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, haloC1-8alkyl, C3-8cycloalkenyl, Ar, or xe2x80x94C1-8hydrocarbyleneAr; or R5 and R6 together with the nitrogen to which they are attached form a pyrrolidino, piperidino, morpholino, or thiomorpholino ring;
each R7 is independently hydrogen, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, haloC1-8alkyl, C3-8cycloalkenyl, Ar, or xe2x80x94C1-8hydrocarbyleneAr;
Ra and Rb, independently, are selected from the group consisting of hydrogen, C1-8alkyl, Ar, C1-3hydrocarbyleneAr, SO2Ar, SO2C1-4 alkyl, (C3-8cycloalkyl)C1-8alkyl, and Het;
Rc is Ar, Het, R7CO2xe2x80x94, R7C(xe2x95x90O)xe2x80x94, R7OC(xe2x95x90O)xe2x80x94, R7Oxe2x80x94, R7C1-8alkyleneOxe2x80x94, R7Sxe2x80x94, R7C(xe2x95x90S)xe2x80x94, R7S(xe2x95x90O)xe2x80x94, R7S(xe2x95x90O)2xe2x80x94, R7SC(xe2x95x90O)xe2x80x94, R7C(xe2x95x90O)N(R7)xe2x80x94, R7C(xe2x95x90S)N(R7)xe2x80x94, R5R6Nxe2x80x94, R5R6NC(xe2x95x90O)xe2x80x94, R5R6NC(xe2x95x90S)xe2x80x94, R5R6NS(xe2x95x90O)xe2x80x94, R5R6NSO2xe2x80x94, R7S(xe2x95x90O)N(R7)xe2x80x94, R7SO2N(R7)xe2x80x94, or R7N(R7)C(xe2x95x90O) N(R7)xe2x80x94;
each Ar is independently aryl or heteroaryl;
p is 0, 1, 2, 3, or 4; and
q is 0, 1, 2, 3, 4, 5, 6, 7, or 8;
wherein any Ar of R1, R3-R7, Ra, Rb and Rc is optionally substituted with one or more (e.g. 1, 2, 3, 4, or 5) substituents independently selected from halo, CN, NO2, ORe, methylenedioxy, ethylenedioxy, CF3, OCF3, SRe, SO2Re, NRfRg, CONRfRg, CORe, Re, and C1-8hydrocarbyleneRd;
each Rd is independently hydroxy, C1-8alkoxy, cyano, SRh, or C(xe2x95x90O)Rh;
each Re is independently selected from the group consisting of hydrogen, C1-8alkyl, Ar, C1-3hydrocarbyleneAr, SO2Ar, SO2C1-4 alkyl, (C3-8cycloalkyl)C1-8alkyl, and Het; wherein any Ar of Re is optionally substituted with one or more (e.g. 1, 2, 3, 4, or 5) substituents independently selected from halo, CN, NO2, ORd, methylenedioxy, ethylenedioxy, CF3, OCF3, SRf, SO2Rf, NRfRg, CONRfRg, CORf, Rf, and C1-8hydrocarbyleneRd;
each Rf and Rg, is independently selected from the group consisting of hydrogen, C1-8alkyl, Ar, C1-3hydrocarbyleneAr, SO2Ar, SO2C1-4 alkyl, (C3-8cycloalkyl)C1-8alkyl, and Het; and
each Rh is independently hydrogen, C1-8alkyl, C1-8alkenyl, C2-8alkynyl, haloC1-8alkyl, C3-8cycloalkenyl, phenyl, or xe2x80x94C1-8hydrocarbylene(phenyl);
or a pharmaceutically acceptable salt thereof.
Preferably, for a compound of formula (I):
I. when
(a) R3 is hydrogen, C1-8alkyl, or optionally substituted phenylC1-8hydrocarbylene-, and
(b) q is 0,
xe2x80x83then either
(i) p is 3 or 4, or
(ii) p is 1 or 2, and R4 is other than halo, C1-8alkyl, or C1-8alkoxy; and
II. when
(a) R3 is hydrogen; and
(b) q is at least 1, and at least one R2 is hydroxy substituted at the 5-position of Formula (I),
xe2x80x83then either
(i) p is 3, or 4; or
(ii) p is 2, one R4 is halo, hydroxy, C1-8alkyl, CF3, CF3O, C1-8alkoxy, or C1-8hydrocarbyleneORa, wherein Ra is hydrogen or C1-6alkyl, and the other R4 is other than C1-8alkyl; or
(iii) at least one R4 is present and is other than halo, hydroxy, C1-8alkyl, CF3, CF3O, C1-8alkoxy, or C1-8hydrocarbyleneORa, wherein Ra is hydrogen or C1-6alkyl; and
III. when
(a) R3 is phenyl or phenyl substituted with one fluoro, chloro, bromo, trifluoromethyl, C1-8alkyl, hydroxy, or OC1-8alkyl;
xe2x80x83then either
(i) p is 3, or 4; or
(ii) p is 2, one R4 is halo, C1-8alkyl, C1-8alkoxy, hydroxy, or trifluoromethyl, and the other R4 is other than C1-8alkyl; or
(iii) at least one R4 is present and is other than a halo, C1-8alkyl, C1-8alkoxy, hydroxy, or trifluoromethyl; and
IV. when
(a) R3 is C1-6alkylenephenyl wherein the phenyl is optionally substituted with fluoro, chloro, bromo, C1-8alkyl, or OC1-8alkyl;
xe2x80x83then either
(i) p is 3, or 4; or
(ii) p is 2, one R4 is fluoro, chloro, bromo, C1-8alkyl, or C1-8alkoxy, and and the other R4 is other than C1-8alkyl; or
(iii) at least one R4 is present and is other than a fluoro, chloro, bromo, C1-8alkyl, or C1-8alkoxy;
More preferably, for a compound of formula (I):
I. when
(a) R3 is hydrogen, C1-8alkyl, or optionally substituted phenylC1-8hydrocarbylene-, and
(b) q is 0,
xe2x80x83then either
(i) p is 3or 4, or
(ii) p is 1 or 2, and R4 is other than halo, C1-8alkyl, or C1-8alkoxy; and
II. when
(a) R3 is hydrogen ArC1-8hydrocarbylene, ArC1-8hydrocarbyleneC(xe2x95x90O)xe2x80x94, C1-8alkyl(Cxe2x95x90O)xe2x80x94, or C1-8alkyl; and
(b) q is at least 1, and at least one R2 is hydroxy substituted at the 5-position of Formula (I),
xe2x80x83then either
(i) p is 3, or 4; or
(ii) p is 2, one R4 is halo, hydroxy, C1-8alkyl, CF3, CF3O, C1-8alkoxy, or C1-8hydrocarbyleneORa, wherein Ra is hydrogen or C1-8alkyl, and the other R4 is other than C1-8alkyl; or
(iii) at least one R4 is present and is other than halo, hydroxy, C1-8alkyl, CF3, CF3O, C1-8alkoxy, or C1-8hydrocarbyleneORa, wherein Ra is hydrogen or C1-8alkyl; and
III. when
(a) R3 is phenyl or phenyl substituted with one halo, trifluoromethyl, C1-8alkyl, hydroxy, or OC1-8alkyl;
xe2x80x83then either
(i) p is 3, or 4; or
(ii) p is 2, one R4 is halo, C1-8alkyl, C1-8alkoxy, hydroxy, or trifluoromethyl, and the other R4 is other than C1-8alkyl; or
(iii) at least one R4 is present and is other than a halo, C1-8alkyl, C1-8alkoxy, hydroxy, or trifluoromethyl; and
IV. when
(a) R3 is C1-6alkylenephenyl wherein the phenyl is optionally substituted with halo, C1-8alkyl, or OC1-8alkyl;
xe2x80x83then either
(i) p is 3, or 4; or
(ii) p is 2, one R4 is halo, C1-8alkyl, or C1-8alkoxy, and and the other R4 is other than C1-8alkyl; or
(iii) at least one R4 is present and is other than halo, C1-8alkyl, or C1-8alkoxy.
Another embodiment of the present invention provides a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
Still another embodiment of the present invention provides a method of treating a disease, disorder, and/or condition in a mammal (e.g., animal or human), wherein a 5-HT receptor is implicated and modulation of a 5-HT function is desired. The method comprises administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the mammal.
Yet another embodiment of the present invention comprises a method of modulating 5-HT receptor function with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
A further embodiment of the present invention provides a method of treating or preventing diseases, disorders, and/or conditions of the central nervous system. The method comprises administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the mammal.
Specific diseases, disorders, and/or conditions for which compounds of Formula (I) may have activity include, but are not limited to, obesity, depression, epilepsy, anxiety, Alzheimers disease, withdrawal from drug abuse, schizophrenia, schizophreniform disorder, schizoaffective disorder, delusional disorder, a stress related disease (e.g., general anxiety disorder), panic disorder, a phobia, obsessive compulsive disorder, post-traumatic-stress syndrome, immune system depression, a stress induced problem with the urinary, gastrointestinal or cardiovascular system (e.g., stress incontinence), neurodegenerative disorders, autism, chemotherapy-induced vomiting, hypertension, migraine headaches, cluster headaches, sexual dysfunction in a mammal (e.g., a human), addictive disorder and withdrawal syndrome, an adjustment disorder, an age-associated learning and mental disorder, anorexia nervosa, apathy, an attention-deficit disorder due to general medical conditions, attention-deficit hyperactivity disorder, behavioral disturbance (including agitation in conditions associated with diminished cognition, e.g., dementia, mental retardation or delirium), bipolar disorder, bulimia nervosa, chronic fatigue syndrome, conduct disorder, cyclothymic disorder, dysthymic disorder, fibromyalgia and other somatoform disorders, generalized anxiety disorder, an inhalation disorder, an intoxication disorder, movement disorder (e.g., Huntington""s disease or Tardive Dyskinesia), oppositional defiant disorder, peripheral neuropathy, post-traumatic stress disorder, premenstrual dysphoric disorder, a psychotic disorder (brief and long duration disorders and psychotic disorder due to medical condition), mood disorder (major depressive or bipolar disorder with psychotic features) seasonal affective disorder, a sleep disorder, a specific developmental disorder, agitation disorder, selective serotonin reuptake inhibition (SSRI) xe2x80x9cpoop outxe2x80x9d syndrome or a Tic disorder (e.g., Tourette""s syndrome). The activity of 5-HT receptors is implicated in the above diseases of the central nervous system.
Yet another embodiment of the present invention comprises the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating or preventing diseases, disorders, and conditions of the central nervous system.
The invention also provides synthetic intermediates and processes disclosed herein that are useful for preparing compounds of formula (I).
Compounds of formula (I) are 5-HT ligands. Thus, radiolabeled compounds of formula (I) are useful as imaging agents for medical therapy and diagnosis. Such radiolabeled compounds are also useful as pharmacological tools for studying 5-HT function and activity. Accordingly, the invention also t provides a radiolabeled compound of formula (I), or a salt thereof.
Compounds of formula I can be labeled using techniques which are well known in the art. For example, a radioisotope can be incorporated into the compound or appended to the compound of formula I using techniques well known in the art. For example, see Arthur Murry III, D. Lloyd Williams; Organic Synthesis with Isotopes, vol. I and II, lnterscience Publishers Inc., N.Y. (1958) and Melvin Calvin et al. Isotopic Carbon John Wiley and Sons Inc., N.Y. (1949). Any radioisotope capable of being detected can be employed as a label. For example, suitable radioisotopes include: carbon-11, fluorine-18, fluorine-19, iodine-123 and iodine-125. Preferably, a compound of formula I may be labeled by appending one or more radioisotopes of a halogen (e.g. iodine-123) to an aromatic ring, or by alkylating a nitrogen of a compound of formula (I) with a group comprising a phenyl group bearing a radioisotope.
The invention also provides a radiolabeled compound of formula (I) for use in medical diagnosis or therapy, as well as the use of a radiolabeled compound of formula (I) to prepare a medicamant useful for medical diagnosis or therapy.
Further aspects and embodiments of the invention may become apparent to those skilled in the art from a review of the following detailed description, taken in conjunction with the examples and the appended claims. While the invention is susceptible of embodiments in various forms, described hereafter are specific embodiments of the invention with the understanding that the present disclosure is intended as illustrative, and is not intended to limit the invention to the specific embodiments described herein.